Project Summary Chloroquine retinopathy is a growing health problem with the increased use of the drug to treat lupus and rheumatoid arthritis. Patients present with a loss of central vision, retinal pigmented epithelium abnormalities, and bull?s eye maculopathy. There is currently no treatment other than to stop giving chloroquine; this limits the long-term treatment of the other diseases, and the retention of chloroquine in pigmented tissues enables progressing loss of vision even after treatment has stopped. While is known to target RPE lysosomes and impair their degradative activity, it remains unclear how this leads to vision loss and how this can be treated. Recently, lysosomes have been identified as playing a critical role in intracellular and extracellular signaling, with lysosomal function extending beyond degradation to calcium signaling and the exocytosis of waste, transmitters and inflammatory signals. This proposal will determine whether these newly identified lysosomal functions are perturbed in chloroquine retinopathy. The ability of chloroquine treatment to alter lysosomal calcium signaling and exocytosis will be assayed first in our in vitro model of chloroquine retinopathy, then confirmed in our newly developed in vivo murine model of chloroquine retinopathy. The proposal will then determine whether treatments developed in recent years to enhance lysosomal pH and calcium regulation prevent the pathological changes induced by chloroquine. The restoration of lysosomal function will be determined using both in vitro and in vivo models. Finally, the ability of these treatments to prevent the loss of vision and photoreceptors in the chloroquine retinopathy mouse will be determined. The results of the project will advance our mechanistic understanding of RPE signaling in health and disease while potentially helping answer a real health need.